Non-aqueous taxane nanodispersion formulations and methods of using the same

ABSTRACT

Non-aqueous, ethanol-free taxane nanodispersion formulations are provided. Nanodispersion formulations of embodiments of the invention include a taxane, an oil, a non-ionic surfactant, a non-aqueous solvent, and an organic acid component, wherein the organic acid component is soluble in the non-aqueous solvent and the amount by weight of non-ionic surfactant is equal to or greater than the amount by weight of non-aqueous solvent. Also provided are methods of using the nanodispersion formulations, as well as kits that include the nanodispersion formulations. Non-aqueous, ethanol-free docetaxel nanodispersion formulations are provided. Nanodispersion formulations of embodiments of the invention include docetaxel, an oil, a non-ionic surfactant, a non-aqueous solvent, and an organic acid which is soluble in the non-aqueous solvent and is substantially free of any conjugate base. Also provided are methods of using the nanodispersion formulations, as well as kits that include the nanodispersion formulations.

INTRODUCTION

This application claims priority from US Provisional Applications61/708,595 and 61/708,586, both filed Oct. 1, 2012, and eachincorporated herein by reference in its entirety.

Taxanes constitute a family of naturally occurring diterpene compoundsincluding paclitaxel. Paclitaxel, originally isolated from the bark ofthe Pacific Yew tree (Taxus brevifolia), and its semi-syntheticanalogue, docetaxel, are two examples of taxane compounds. Taxanes areactive agents that block cell growth by stopping mitosis via microtubuleinterference.

Taxanes can be used effectively to treat a variety of cancers and havebeen reported to have therapeutic effects in treating certaininflammatory diseases. Paclitaxel, for example, has been found to haveactivity against ovarian and breast cancers, as well as againstmalignant melanoma, colon cancer, leukemias and lung cancer (see, e.g.,Borman, Chemical & Engineering News, Sep. 2, 1991, pp. 11-18; ThePharmacological Basis of Therapeutics (Goodman Gilman et al., eds.),Pergamon Press, New York (1990), p. 1239: Suffness, Antitumor Alkaloids,in: “The Alkaloids, Vol. XXV,” Academic Press, Inc. (1985), Chapter 1,pp. 6-18: Rizzo et al., J. Pharm. & Biomed. Anal. 8(2):159-164 (1990);and Biotechnology 9:933-938 (October, 1991).

Formulation of taxanes in therapeutically useful carriers, so as toenable the taxanes to be administered to animals, is made difficult bythe nature of the taxane molecule, which can be poorly soluble in bothaqueous and lipid carriers.

Docetaxel is an antineoplastic agent belonging to the taxoid family. Itis prepared by semisynthesis beginning with a precursor extracted fromthe renewable needle biomass of yew plants. The chemical name fordocetaxel is (2R,3S)—N-carboxy-3-phenylisoserine, Ntert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate. Decetaxcel has the following structural formula:

Docetaxel can be used effectively to treat a variety of cancers and hasbeen reported to have a therapeutic effect in treating certaininflammatory diseases. For example, docetaxel has been found to haveactivity against breast cancer, non-small cell lung cancer, prostatecancer, gastric adenocarcinoma and head and neck cancer.

However, docetaxel is highly lipophilic and practically insoluble inwater. This makes the formulation of docetaxel in therapeutically usefulcarriers a challenge.

SUMMARY

Non-aqueous, ethanol-free taxane liquid nanodispersion formulations areprovided. The nanodispersion formulations include a taxane, an oil, anon-ionic surfactant, a non-aqueous solvent, and an organic acidcomponent, wherein the organic acid component is soluble in thenon-aqueous solvent and the amount by weight of non-ionic surfactant isequal to or greater than the amount by weight of non-aqueous solvent.Also provided are methods of using the nanodispersion formulations, aswell as kits that include the nanodispersion formulations.

Non-aqueous, ethanol-free taxane liquid nanodispersion formulations areprovided. The nanodispersion formulations include a taxane, an oil, anon-ionic surfactant, a non-aqueous solvent, and an organic acidcomponent, wherein the organic acid component is soluble in thenon-aqueous solvent and the amount by weight of non-ionic surfactant isequal to or greater than the amount by weight of non-aqueous solvent.Also provided are methods of using the nanodispersion formulations, aswell as kits that include the nanodispersion formulations. Additionally,provided herein is a non-aqueous, ethanol-free docetaxel liquidnanodispersion formulation comprising docetaxel, an oil, a non-ionicsurfactant, a non-aqueous solvent and an organic acid, wherein saidorganic acid is soluble in the non-aqueous solvent and is substantiallyfree of any conjugate base. Also provided are methods of using thenanodispersion formulations, as well as kits that include thenanodispersion formulations.

DETAILED DESCRIPTION Taxane Nanodispersion Formulations

Non-aqueous, ethanol-free taxane liquid nanodispersion formulations areprovided. The nanodispersion formulations include a taxane, an oil, anon-ionic surfactant, a non-aqueous solvent, and an organic acidcomponent, wherein the organic acid component is soluble in thenon-aqueous solvent and the amount by weight of non-ionic surfactant isequal to or greater than the amount by weight of non-aqueous solvent.Also provided are methods of using the nanodispersion formulations, aswell as kits that include the nanodispersion formulations.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about”. The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely”, “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In the following sections, the taxane nanodispersion formulations andtaxane diluted solutions prepared therefrom, as well as methods usingthe same, are described in greater detail, as well as methods forpreparing the nanodispersion formulations and diluted solutions, as wellas kits that may include the formulations.

Aspects of the invention include taxane nanodispersion formulations. Insome instances, the nanodispersion formulations are non-aqueous liquid,ethanol-free compositions that, upon combination with an aqueous medium,produce a taxane diluted solution. The non-aqueous, ethanol-free taxaneliquid nanodispersion formulations of embodiments of the inventioncomprise a taxane, an oil, a non-ionic surfactant, a non-aqueoussolvent, and an organic acid component, wherein the organic acidcomponent is soluble in the non-aqueous solvent and the amount by weightof non-ionic surfactant is equal to or greater than the amount by weightof non-aqueous solvent. In certain embodiments, the non-aqueous,ethanol-free taxane liquid nanodispersion formulations of embodiments ofthe invention consist essentially of a taxane, an oil, a non-ionicsurfactant, a non-aqueous solvent, and an organic acid component,wherein the organic acid component is soluble in the non-aqueous solventand the amount by weight of non-ionic surfactant is equal to or greaterthan the amount by weight of non-aqueous solvent.

As used herein, the term “nanodispersion” refers a substantially clear(i.e., transparent) solution comprising nanosized particles. In someinstances, the particle size ranges from about 3 to about 70 nm, fromabout 5 to about 50 nm, from about 7 to about 30 nm, or from about 8 toabout 15 nm.

Taxanes of interest are diterpene compounds. In some instances, taxanesare compounds described by the formula:

Of interest are anhydrous taxanes as well as hydrates thereof, e.g.,mono, di, tri, tetra and penta hydrates, etc. In certain embodiments,the taxane is paclitaxel or docetaxel, including anhydrous or a hydratethereof, e.g., anhydrous docetaxel, docetaxel trihydrate, paclitaxeltrihydrate, etc., may be employed in the formulations. Taxanes ofinterest also include, but are not limited to: 7-epitaxol, 7-acetyltaxol, 10-desacetyl-taxol, 10-desacetyl-7-epitaxol, 7-xylosyltaxol,10-desacetyl-7-glutaryltaxol, 7-N,N-dimethylglycyltaxol,7-L-alanyltaxol, SB-T-1011, etc. The taxane may be present as a freebase or salt.

Taxane nanodispersion formulations include an effective amount of ataxane. By effective amount is meant a dosage sufficient to provide thedesired result, e.g., inhibition of cellular proliferation. Theeffective amount of taxane may vary depending on the particular taxaneemployed, and in certain embodiments ranges from 0.05 to 5% by weight,such as 0.5 to 5% by weight and including 0.3 to 3% by weight. Incertain embodiments, the nanodispersion formulations include aneffective amount of paclitaxel or paclitaxel trihydrate. In certainembodiments, paclitaxel or paclitaxel trihydrate is present in thenanodispersion formulation in an amount ranging from 0.05 to 5.0% w/w,such as 0.5 to 5.0% w/w, and including 0.3 to 3.0% w/w, where in someinstances the amount ranges from 0.3 to 5.0% w/w, such as 0.3 to 3.0%w/w, e.g., 0.4 to 2.5% w/w, e.g., 0.5 to 2.0% w/w, and including 1.0 to1.5% w/w. In certain embodiments, the nanodispersion formulationsinclude an effective amount of docetaxel or docetaxel trihydrate. Incertain embodiments, anhydrous docetaxel or docetaxel trihydrate ispresent in the nanodispersion formulation in an amount ranging fromabout 0.1 to about 5 wt %, or from about 0.5 to about 5 wt %, or fromabout 0.5 to about 3 wt %, or from about 1 to about 3 wt %, or is about2 wt %. The concentration of the taxane in the formulations may vary,and is in some embodiments, about 30 mg/ml or less, about 25 mg/ml orless, about 20 mg/ml or less, about 10 mg/ml or less, about 1 mg/ml orless, or ranges from about 0.05 to about 20 mg/ml, from about 0.5 toabout 20 mg/ml, from about 1 to about 20 mg/ml, or from about 5 to about20 mg/ml.

As used herein, the term “non-aqueous” is intended to refer toformulations having a water content about 3% by weight or less. Thewater content may come from any one or more of the components in theformulation, such as the organic acid component or from the waterassociated with docetaxel trihydrate, when used. In some embodiments,the formulations comprise less than about 3% water by weight, or lessthan about 2.5% water by weight, or less than about 2% water by weight,or less than about 1.5% water by weight, or less than about 1% water byweight, or less than about 0.5% water by weight, or less than about 0.1%water by weight, or less than about 0.01% water by weight, or than about0.005% water by weight.

Also present in the nanodispersion formulations is an oil component madeup of one or more oils. Without wishing to be bound by any one theory,it is contemplated that the inclusion of the oil in the nanodispersionformulation helps stabilize the diluted solution. Oils of interest arephysiologically acceptable and include, but are not limited to: simplelipids, derived lipids, complex lipids that are derived from vegetableoil and fat, animal oil and fat, or mixtures thereof, where the oils maybe naturally occurring or synthetic.

In certain embodiments, the oil includes, but is not limited tovegetable oil such as soybean oil, olive oil, sesame oil, castor oil,corn oil, peanut oil, safflower oil, grape seed oil and eucalyptus oil,medium-chain fatty acid esters, low-chain fatty acid esters,triglycerides, and the like. Animal oils and fat of interest include,but are not limited to, cod-liver oil, seal oil, sardine oil,docosahexiaenoic acid, and eicosapentaenoic acid. One or a combinationof more than one of these types of oils can be used. For example, someembodiments of the subject formulations include soybean oil, olive oil,sesame oil, or combinations thereof. Other embodiments include soybeanoil, olive oil, or combinations thereof. Highly refined oils and fatsare employed in certain embodiments. In some embodiments, the oil issoybean oil. In some embodiments, the oil is a medium chain triglyceride(i.e., a medium chain fatty acid ester). In some embodiments, the oil isnot a medium chain triglyceride (i.e., a medium chain fatty acid ester).

Oils to be used in the formulations disclosed herein may also includetocopherols. Tocopherols are a family of natural and syntheticcompounds, also known by the generic names tocols or Vitamin E.α-Tocopherol is the most abundant and active form of this class ofcompounds and it has the following chemical structure:

Other members of this class include α-, β-, γ-, and δ-tocotrienols, andα-tocopherol derivatives such as tocopherol acetate, phosphate,succinate, nitotinate and linoleate. Any convenient tocopherol may bepresent, as desired, including the specific tocopherols listed above.

Oils of interest also include polyol esters of medium chain fatty acids.The term “polyol esters of medium chain fatty acids” is intended toinclude esters and mixed esters of glycerol, propylene glycol or otheropen chain polyols such as polyethylene glycol, reacted with mediumchain fatty acids, e.g., where the acid has a chain length between 6 and12 carbon atoms. In some instances, the polyol esters of medium chainfatty acids are triglycerides or diglycerides of the C₈-C₁₀ fatty acids,e.g., as may be commercially available from the fractionation of coconutoil. Commercially available products of this description are sold underthe trade names “NEOBEE®”, “ODO®”, “Panacet®”, “Miglyol®” and “Captex®300” and have a majority of C₈ fatty acid (caprylic) triglyceride andC₁₀ fatty acid (capric) triglyceride with minor levels of C₆ and C₁₄fatty acid triglycerides. In some embodiments, the oil is NEOBEE®.

In certain embodiments, the oil is selected from the group consisting ofsynthetic oils, vegetable oils, tocopherols and combinations thereof. Inother embodiments, the oil is selected from the group consisting ofsoybean oil, olive oil, sesame oil, corn oil, a medium chaintriglyceride, a tocopherol or derivative thereof and combinationsthereof.

In certain embodiments, the oil is about 20 wt % or less of theformulation. In some instances, the amount of oil in the nanodispersionformulation ranges from about 0.5 to about 20 wt %, or from about 1 toabout 20 wt %, or from about 1 to about 10 wt %. In certain embodiments,the oil is present in an amount ranging from about 1 to about 5 wt %. Inother embodiments, the oil is present in an amount ranging from about 1to about 3 wt %, or about 2 wt %. In certain embodiments, the amount ofoil in the nanodispersion formulation is calculated based on the amountof docetaxel in the formulation. For example, in some embodiments, whenthe amount of oil greatly exceeds the amount of docetaxel (w/w), theparticle size can become larger, which typically results in theformulation becoming cloudy. Accordingly, in some embodiments, theamount of oil is less than about three times the amount of taxane (w/w),or equal to or less than about 2.5 times the amount of taxane (w/w), orequal to or less than about 2 times the amount of taxane (w/w), or equalto or less than about 1.5 times the amount of taxane (w/w), or is aboutequal to the amount of taxane (w/w), or is about half of the amount oftaxane (w/w).

Also present in the nanodispersion formulations is a non-ionicsurfactant, which may include one or more non-ionic surfactants.Surfactants of interest include any type of non-ionic surfactant thatcan be used for pharmaceutical formulations. Non-ionic surfactants ofinterest include, but are not limited to, polyoxyalkylene copolymer, andsorbitan fatty acid esters. In some embodiments, the sorbitan fatty acidester is a polyoxyethylene sorbitan fatty acid ester (e.g.,polyoxyethylene sorbitan tristearate (Tween® 65); polyoxyethylenesorbitan trioleate (Tween® 85); polyethylene glycol 400 monostearate;polysorbate 60; (Tween® 60); polyoxyethylene monostearate (Myrj® 49);polysorbate 80 (Tween® 80); polysorbate 40 (Tween® 40); and polysorbate20 (Tween 20)) or sorbitan fatty acid esters (e.g., sorbitan trioleate(Span® 85); sorbitan tristearate (Span® 65); sorbitan sesquioleate(Arlacel® 83); glyceryl monostearate; sorbitan monooleate (Span® 80);sorbitan monostearate (Span® 60); sorbitan monopalmitate (Span® 40); andsorbitan monolaurate (Span® 20)). In some embodiments, the non-ionicsurfactant is polysorbate 80. In some embodiments, the polysorbate 80 isrefined grade.

The amount of non-ionic surfactant in the nanodispersion formulation mayvary. In some instances, the amount of non-ionic surfactant in thenanodispersion formulation is 40 wt % or more. In some instances, thenon-ionic surfactant is present in an amount ranging from about 40 toabout 75 wt %, or from about 50 to about 65 wt %, or from about 50 toabout 60 wt %, or from about 50 to about 57 wt %, or from about 57 toabout 65 wt %. The combination ratio by weight of the oil and thesurfactant in the subject nanodispersion formulations may vary, and isin some instances about 1/100, or 1/50, or 1/40, or 1/30, or 1/20, or1/10, or 1/8, or 1/6, or 1/4, or 1/2, or 1/1.

The nanodispersion formulations of the invention further include anon-aqueous solvent, which may include one or more non-aqueous solvents.Non-aqueous solvents of interest include, but are not limited to,propylene glycol, polypropylene glycol, polyethylene glycol (such as PEG300, PEG 400, PEG 600, PEG 800, PEG 1000, etc., where in certainembodiments polyethylene glycols, when employed, have an averagemolecular weight of 1000 or less), glycerin, triacetin, dimethylisosorbide, glycofurol, propylene carbonate, dimethyl acetamide or amixture thereof. In some embodiments, the non-aqueous solvent ispolyethylene glycol. In some embodiments, the non-aqueous solvent ispolyethylene glycol 400. In some embodiments, the polyethylene glycolhas a melting point of less than 0° C. In some embodiments, thenon-aqueous solvent is polyethylene glycol 300.

The non-aqueous solvent may be present in varying amounts, and in someinstances is present in an amount ranging from about 20 to about 60 wt%, or from about 35 to about 45 wt %, including amounts ranging fromabout 35 to about 40 wt %, or from about 40 to about 45 wt %.

In the present formulations, the amount of non-ionic surfactant (w/w)should be about equal to or greater than the amount of non-aqueoussolvent (w/w) in the formulation, or greater than about 95% of theamount of non-aqueous solvent (w/w), or in other words, the ratio byweight of the non-ionic surfactant and the non-aqueous solvent is 0.95or more. As shown in the Examples, when used in such amounts, thestability of the formulation is enhanced.

In the present nanodispersions, the combination ratio by weight of theoil and the non-aqueous solvent in the nanodispersion formulations mayvary, and in some instances is 1/100, or 1/50, or 1/40, or 1/30, or1/20, or 1/10, or 1/7, or 1/5, or 1/3, or 1/1.

The nanodispersion formulation further comprises an organic acidcomponent. An organic acid component may include an organic acid and/oran organic acid buffer (i.e., an organic acid and its conjugate base (orsalt thereof)). Therefore, in some instances, the organic acid buffercomprises an organic acid and a salt of its conjugate base. Organicacids of interest upon which the organic acid component may be basedinclude those which are soluble in the non-aqueous solvent (in theamount used). Specific examples include lactic acid, succinic acid,malic acid, tartaric acid and acetic acid.

In some instances, the organic acid component is a lactic acid/sodiumlactate component, such that the component includes both lactic acid andsodium lactate. As organic acid can be hydroscopic and may contain asmall or trace amount of water, the lactic acid and/or sodium lactatecan be commercially available or substantially dehydrated prior to use.In some instances, the lactic acid/sodium lactate component is presentin an amount ranging from about 0.3 to 3 wt %, or from about 0.3 toabout 2 wt %, or from about 0.3 to about 1.5 wt %, or from about 0.5 toabout 1.5 wt %, or from about 0.8 to about 1.2 wt %, or from about 0.8to about 1 wt %, or about 1 wt %.

In other instances, the organic acid component, e.g., lactic acid oracetic acid, does not contain any significant amount of its conjugatebase (or salt thereof). In addition, in some embodiments, thenanodispersion formulations disclosed herein do not contain a buffer ora mineral acid. In some embodiments, the organic acid component islactic acid. The lactic acid can be D- or L-lactic acid, or a mixturethereof. The organic acid may be present in varying amounts, and in someinstances is present in an amount ranging from about 0.3 to about 3 wt%, or from about 0.3 to about 1 wt %, or from about 0.3 to about 0.6 wt%, or from about 0.4 to about 0.5 wt %, or from about 0.5 to about 1 wt%, or from about 0.7 to about 1 wt %, or about 0.8 wt %.

In some embodiments, the present disclosure provides for a non-aqueous,ethanol-free docetaxel liquid nanodispersion formulation comprising:docetaxel, soybean oil in an amount ranging from about 1 to about 5 wt%, polysorbate 80 in an amount ranging from about 50 to about 60 wt %,polyethylene glycol in an amount ranging from about 35 to about 45 wt %,and lactic acid or lactic acid buffer in an amount ranging from 0.3 to 1wt %, wherein the amount by weight of non-ionic surfactant is equal toor greater than the amount by weight of non-aqueous solvent.

In another embodiment, the present disclosure provides for anon-aqueous, ethanol-free docetaxel liquid nanodispersion formulationcomprising: docetaxel, a medium chain triglyceride in an amount rangingfrom about 1 to about 5 wt %, polysorbate 80 in an amount ranging fromabout 50 to about 60 wt %, polyethylene glycol in an amount ranging fromabout 35 to about 45 wt %, and lactic acid or lactic acid buffer in anamount ranging from 0.3 to 1 wt %, wherein the amount by weight ofnon-ionic surfactant is equal to or greater than the amount by weight ofnon-aqueous solvent.

The nanodispersion formulation as described above typically has a pH ofless than about 4, or less than about 3.5, or less than about 3.4, orless than about 3.3, or less than about 3.25, or less than about 3.2, orless than about 3.1, or from about 3.0 to about 3.1.

Methods of Preparing Taxane Nanodispersion Formulations

Nanodispersion formulations may be prepared according to any convenientprotocol. As such, the components of the desired nanodispersion may becombined under conditions sufficient to produce the desirednanodispersion. Accordingly, an amount of taxane, oil, non-ionicsurfactant, non-aqueous solvent, and organic acid component, wherein theorganic acid component is soluble in the non-aqueous solvent and theamount by weight of non-ionic surfactant is equal to or greater than theamount by weight of non-aqueous solvent, may be combined underconditions sufficient to produce a nanodispersion. The components may becombined in any convenient order. The components may be combined at anyconvenient temperature, e.g., room temperature or elevated temperatures,such as temperatures ranging from 30 to 95° C., or 50 to 60° C., or 70to 80° C. Certain of the components may be combined with each other, andthen combined together, or all of the components may be combined atsubstantially the same time. Combination may include various manners ofagitation or mixing, e.g., stirring, sonication, etc., in order toproduce the nanodispersion. Depending on the particular preparationmethod, an aqueous solvent, e.g., water, etc. may or may not be employedduring preparation of the nanodispersion compositions.

In one embodiment, a nanodispersion is prepared without an aqueoussolvent. In these embodiments, the desired amounts of components of thenanodispersion, e.g., taxane, oil, non-ionic surfactant, non-aqueoussolvent, and organic acid component are combined. Combination mayinclude various manners of agitation, e.g., stirring, sonication, etc.,in order to produce the nanodispersion. Where desired, heat may beemployed to facilitate mixing, although, in some embodiments, thecombining is performed at ambient temperature. In certain embodiments,the nanodispersion is clear. By clear is meant that the nanodispersionis a translucent, if not transparent liquid, i.e., the liquid ispellucid.

In some instances, the nanodispersion preparation protocol includes useof an aqueous solvent, e.g., pure water. In these instances, an aqueousformulation is prepared, which includes taxane, oil, non-ionicsurfactant, non-aqueous solvent, organic acid component and an aqueoussolvent, e.g., water, etc. In certain embodiments, the aqueousformulation composition is clear. By clear is meant that thenanodispersion is a translucent, if not transparent liquid, i.e., theliquid is pellucid. As such, the initial preparation is not cloudy. Insome instances, the particle size of the initial composition ranges fromabout 3 to about 70 nm, such as about 5 to about 50 nm and includingabout 7 to about 30 nm, such as about 8 to about 15 nm. Of interest incertain embodiments are initial compositions that are clear (e.g., asdescribed above) and have a particle size of about 70 nm or less, suchas about 50 nm or less, including about 30 nm or less, including about25 nm or less, about 20 nm or less and about 15 nm or less. In theseembodiments, as a final step, water may be removed from the compositionto produce a final, non-aqueous nanodispersion. Removal of water may beaccomplished using any convenient protocol, e.g., via a combination ofpressure and/or temperature modulation, such as heating.

The preparation methods can be carried out at certain temperature suchas temperatures ranging from about 30° C. to about 95° C., about 50° C.to about 60° C., about 60° C. to about 70° C., or about 70° C. to about80° C. Specific examples are provided in the Experimental section,below.

In some embodiments, the method for making the ethanol-free taxanenanodispersion formulation as disclosed herein does not comprise theaddition of water and/or ethanol, followed by removal thereof.Accordingly, since the non-aqueous, ethanol-free taxane nanodispersionformulation has not been contacted with either water or ethanol duringthe formulation process, it is substantially free of water (i.e, lessthan about 3%) and free of ethanol. In some embodiments, the formulationis essentially free of water (i.e, less than about 1%). In addition, incertain embodiments, the formulations do not have any detectable amountof ethanol. This results in a formulation which is stable and can besuitable for subjects having an adverse reaction to ethanol. In someembodiments, the formulations do not contain activated carbon.

Where desired, an amount of the nanodispersion may be loaded into anindividual dosage container, e.g., vial, which holds the nanodispersionand keeps it sterile during shipping, storage, and handling. Before orduring the loading stage, the nanodispersion can be passed through asub-micron sterilizing filter, e.g., a 0.2μ hydrophilic filter) whichhas a sufficiently small pore size to remove any bacteria or viruses.The sterilizing filters of interest include, but are not limited tohydrophilic filters. In some embodiments, the filter could be a CA(Cellulose Acetate) membrane filter, PTFE (Polytetrafluoroethylene)membrane filter, PVDF (Polyvinylidene fluoride or polyvinylidenedifluoride) membrane filter or PES (Polyethersulfone) membrane filter.

As used herein, the term “vial” refers to any container that is used tohold the nanodispersion formulation. Many pharmaceutical vials are madeof clear glass, which allows several advantages, including visualinspection of the enclosed drug (to ensure that it is still in a clean,non-caramelized, non-collapsed form, when it is ready for use) and ofthe container itself (to ensure that it does not have a hairline crackin one of the walls, which could jeopardize or destroy sterility of theenclosed drug). Various types of pharmaceutical vials are known.Single-chamber vials can be sealed with rubber or plastic plugs thatwill allow a hypodermic needle to be pushed through the rubber seal.Examples include any hydrolytically stable glass, such as a borosilicateType I or soda-lime-silica Type II glass vial, having a suitable stopper(e.g., Teflon coating). Alternately, a single-chamber vial can be madeof a brittle and easily breakable material, inside a sealed bag that cancontain an aqueous solution (such as physiological saline or a dextrosesolution, in an intravenous infusion bag); if this type of vial isbroken, it will release its contents into the still-sealed bag, formixing. In yet other embodiments, two-chamber vials or analogousstructures, e.g., as described in Published United States ApplicationPublication No. 2003/0099674 and U.S. Pat. No. 4,781,354 may beemployed. Other methods for preparing the taxane formulations disclosedherein can be found in Published United States Application PublicationNo. 2011/0269829, the entirety of which is incorporated herein byreference.

Where desired, the nanodispersion formulation may be stored for a periodof time prior to combination with the aqueous medium. This storage timeof the nanodispersion may vary, where storage times may be 1 year ormore, such as 2 years or more, including 3 years or more. While thestorage conditions may vary, in certain instances the storage conditionsare characterized by a temperature ranging from about 5 to 60° C., e.g.,5° C., such as about 8 to 40° C., e.g., about 25° C. The activity of thetaxane active agent is substantially preserved during the storageperiod, such that the nanodispersion formulations are storage stable. Assuch, the activity of the taxane active agent in the infusion solutionfollowing storage is substantially the same as that in thenanodispersion prior to being dried, where the magnitude of anydifference in activity between the nanodispersion and diluted solutionmay be about 15% or less, such as about 10% or less, including about 5%or less, e.g., as can be measured by HPLC.

As shown in the Examples, the nanodispersion formulation according thepresent disclosure is stable for at least 6 months (see Examples 3 and6) at 40° C. The stability of the present nanodispersion formulationscan be determined by methods known in the art, such as by measuring therecovery rate for the taxane (e.g., docetaxel) peak by HPLC. In someembodiments, the nanodispersion formulation exhibits a taxane (e.g.,docetaxel) recovery rate of more than about 95% after 6 months at about40° C., or about 96% or more, or more than about 97% or more, or morethan about 98% or more, or about 99% or more. The recovery rate iscalculated based on the measured amount of docetaxel in the formulation,which is not necessarily the amount of docetaxel added to theformulation (thus eliminating any potential error from an impurity inthe docetaxel).

Taxane Diluted Solutions and Methods of Use

Following preparation of the nanodispersion formulation, e.g., asdescribed above, at the time of desired administration to a subject, adosage amount of the nanodispersion may be combined with an aqueousmedium to prepare an diluted solution that is suitable for use. Thedosage amount of the nanodispersion formulation may be combined with anysuitable aqueous medium, where aqueous mediums of interest include, butare not limited to: deionized water, USP water for injection (WFI),salines, transfusion solutions, physiological solutions, etc. In someembodiments, the aqueous medium comprises an aqueous 0.9% sodiumchloride solution or an aqueous 5% dextrose or glucose solution. Theliquids to nanodispersion (high viscous liquid) ratio employed duringpreparation of the diluted solution may vary, and in certain embodimentsranges from about 0.5 to about 300, such as about 1 to about 100, about2 to about 50 or about 2 to about 20, and including about 2 to about 10.In some instances, the dosage amount of nanodispersion formulation thatis combined with the aqueous medium ranges from about 100 to about 1200g, such as about 300 to about 600 g and the amount of aqueous mediumthat is combined with the dosage amount ranges from about 100 to about1200 ml, such as about 250 to about 600 ml.

The diluted solution prepared from the nanodispersion formulations areliquid preparations that are a suspension of small particles (i.e.,globules) of one liquid in a second liquid with which the first liquidwill not mix. The water present in the taxane diluted solutions may beany convenient water, including deionized water, USP water for injection(WFI), etc.

The combination protocol may vary, where agitation may be employed,e.g., by stirring, by kneading a bag that includes both thenanodispersion and the aqueous medium, etc.

The diluted solutions include a taxane, an oil component, a non-ionicsurfactant component, a non-aqueous solvent component and an aqueousmedium. In certain embodiments, the diluted solutions are clear. Byclear is meant that the diluted solution is a translucent, if nottransparent liquid, i.e., the liquid is pellucid. As such, the dilutedsolution is not cloudy, e.g., as a suspension may appear. Furtherdetails regarding the diluted solutions that may be prepared from thetaxane nanodispersion precursors are provided below. In some instances,the particle size of the final diluted solution ranges from about 3 toabout 70 nm, such as about 5 to about 50 nm and including about 7 toabout 30 nm, such as about 8 to about 15 nm. Of interest in certainembodiments are diluted solutions that are clear (e.g., as describedabove) and have a particle size of about 70 nm or less, such as about 50nm or less, including about 30 nm or less, including about 25 nm orless, about 20 nm or less and about 15 nm or less. In some instances,any difference in particle size between the nanodispersion and dilutedsolutions is minimal, such that the particle sizes in the nanodispersionand diluted solutions are substantially the same. In some instances, anydifference in particle size between the nanodispersion and dilutedsolutions is about 30 nm or less, such as about 20 nm or less, about 15nm or less, about 10 nm or less, or about 5 nm or less. Without wishingto be bound by any one theory, it is contemplated that the inclusion ofthe oil in the nanodispersion formulations helps stabilize the dilutedsolution.

The diluted solutions have a physiologically acceptable pH. In certainembodiments, the pH of the diluted solutions ranges from about 2.5 toabout 8, such as from about 3 to about 7, including from about 3.5 toabout 6. The diluted solutions are substantially clear (i.e.,transparent) formulations. The concentration of the taxane in thediluted solutions may vary, ranging in some embodiments from about 0.05to about 10 mg/ml, such as about 0.2 to about 3 mg/ml.

Methods of using the diluted solutions include administering aneffective amount of the diluted solutions to a subject in order to treatthe subject for a target condition of interest. By “treating” or“treatment” is meant at least a suppression or an amelioration of thesymptoms associated with the condition afflicting the subject, wheresuppression and amelioration are used in a broad sense to refer to atleast a reduction in the magnitude of a parameter, e.g., symptom,associated with the condition being treated, such as pain. As such,treatment also includes situations where the condition is completelyinhibited, e.g., prevented from happening, or stopped, e.g., terminated,such that the subject no longer experiences the condition. As such,treatment includes both preventing and managing a condition.

In practicing the methods, the diluted solutions disclosed herein can beparenterally administered to a subject. By “parenteral administration”is meant administration by a protocol that delivers a quantity of thediluted solutions to the subject, e.g., a patient suffering from acellular proliferative disease, by a route other than the digestivetract. Examples of parenteral administration include, but are notlimited to, intramuscular injection, intravenous injection, and thelike. In certain embodiments, parenteral administration is by injectionusing an injection delivery device.

The amount of diluted solution that is administered to the subject mayvary depending on a number of factors, such as patient specifics, natureof condition, nature of taxane active agent, etc. In certainembodiments, the volume of diluted solution that is administered to asubject may range from about 100 to about 1000 ml, such as about 200 toabout 600 ml. The time period over which this volume is administered mayvary, ranging from about 0.5 to about 6 hr, such as from about 1 toabout 3 hours. Dosages administered to a subject during a givenprocedure may also vary, ranging in some instances from about 20 toabout 500 mg/m², such as from about 50 to about 300 mg/m².

Accordingly, provided herein are methods of administering annon-aqueous, ethanol-free taxane liquid nanodispersion formulation to asubject, the method comprising: (a) combining the non-aqueous,ethanol-free taxane liquid nanodispersion formulation according to thepresent disclosure with an aqueous medium to provide a diluted solution;and (b) administering the diluted solution to the subject.

In some embodiments, the method of using the nanodispersion formulationdisclosed herein comprises the steps of: (a) aseptically withdrawing thedesired amount of the nanodispersion formulation (such as a formulationcomprising about 20 mg taxane/mL) with a calibrated syringe, (b)injecting said formulation into a 250 mL infusion bag or bottle ofeither 0.9% sodium chloride solution or 5% dextrose solution to providea diluted solution having a final taxane concentration of from about 0.3mg/mL to about 0.74 mg/mL, and (c) administering said diluted solutionto a patient. If a dose greater than 200 mg of taxane is required, onemay use a larger volume of the infusion vehicle so that a concentrationof 0.74 mg/mL taxane is not exceeded.

In certain embodiments, the subject methods include a diagnostic step.Individuals may be diagnosed as being in need of the subject methodsusing any convenient protocol. In addition, individuals may be known tobe in need of the subject methods, e.g., they are suffering from atarget disease condition (e.g., cellular proliferative disease, prior topracticing the subject methods. Diagnosis or assessment of targetcondition can be performed using any convenient diagnostic protocol.

Methods of the invention may further include assessing the efficacy ofthe treatment protocol that includes administration of the taxanediluted solution. Assessing the efficacy of treatment may be performedusing any convenient protocol.

Taxane diluted solutions of the invention may be administered to avariety of different types of subjects. Subjects of interest include,but are not limited to: mammals, both human and non-human, including theorders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guineapigs, and rats), lagomorpha (e.g. rabbits) and primates (e.g., humans,chimpanzees, and monkeys). In certain embodiments, the subjects, e.g.,patients, are humans.

In determining whether to administer the diluted solution to aparticular given subject, care will be taken to ensure that theformulation is not contraindicated for that subject. As such, symptomsof the subject may be assessed to ensure that administration of thediluted solution will not have adverse effects that outweigh any benefitthat the diluted solution may provide.

Utility

The subject formulations, diluted solutions and/or methods find use in avariety of applications, including the treatment of subjects sufferingfrom cellular proliferative disease conditions. Cellular proliferativediseases that may be treated with formulations of the invention include,but are not limited to: carcinomas, myelomas, neuroblastomas, orsarcomas, of the brain, breast, lung, colon, prostate or ovaries, aswell as leukemias or lymphomas. Specific disease conditions of interestinclude, but are not limited to, human ovarian cancer, breast cancer,malignant lymphoma, lung cancer, melanoma, and Kaposi's sarcoma.

Kits

Also provided are kits that find use in practicing the subject methods,as described above. For example, kits for practicing the subject methodsmay include a quantity of the nanodispersion formulation, present inunit dosages, e.g., vials, or a multi-dosage format. As such, in certainembodiments, the kits may include one or more unit dosages (e.g., vials)of the nanodispersion formulation. The term “unit dosage”, as usedherein, refers to physically discrete units suitable as unitary dosagesfor human and animal subjects, each unit containing a predeterminedquantity of the subject nanodispersion formulation calculated in anamount sufficient to produce the desired effect. The amount of the unitdosage of the subject formulation depends on various factors, such asthe particular active agent employed, the effect to be achieved, and thepharmacodynamics associated with the active agent in the subject. In yetother embodiments, the kits may include a single multi-dosage amount ofthe formulation.

In certain embodiments, the kits may further include an amount of anaqueous medium suitable for use in production of the diluted solution.The aqueous medium may be any convenient aqueous medium, such asdescribed above, present in any suitable container, e.g., an IV bag.

In some embodiments, the kits may include a syringe which is suitable toprepare the docetaxel diluted solution. A syringe with graduations ispreferred to measure a certain amount of the docetaxel nanodispersion.

In addition to the above components, the subject kits may furtherinclude instructions for practicing the subject methods. Theseinstructions may be present in the subject kits in a variety of forms,one or more of which may be present in the kit. One form in which theseinstructions may be present is as printed information on a suitablemedium or substrate, e.g., one or more pieces of paper on which theinformation is printed, in the packaging of the kit, in a packageinsert, etc. The instructions may be present on a computer readablemedium, e.g., diskette, CD, DVD, etc., on which the information has beenrecorded. The instructions may be present on a website, which may beused via the internet to access the information at a removed site. Otherconvenient means are possible and may be included in the kits.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Docetaxel Nanodispersion Formulations

Aspects of the invention include docetaxel nanodispersion formulations.In some instances, the nanodispersion formulations are non-aqueous,ethanol-free docetaxel liquid compositions that, upon combination withan aqueous medium, produce a docetaxel diluted solution. The non-aqueousliquid nanodispersion formulations of embodiments of the inventioncomprise docetaxel, an oil, a non-ionic surfactant, a non-aqueoussolvent and an organic acid, wherein said organic acid is soluble in thenon-aqueous solvent and is substantially free of any conjugate base. Incertain embodiments, the non-aqueous liquid nanodispersion formulationsof embodiments of the invention consists essentially of docetaxel, anoil, a non-ionic surfactant, a non-aqueous solvent and an organic acid,wherein said organic acid is soluble in the non-aqueous solvent and issubstantially free of any conjugate base.

As used herein, the term “nanodispersion” refers a substantially clear(i.e., transparent) solution comprising nanosized particles. In someinstances, the particle size ranges from about 3 to about 70 nm, fromabout 5 to about 50 nm, from about 7 to about 30 nm, or from about 8 toabout 15 nm.

Anhydrous docetaxel as well as hydrates thereof, e.g., mono, di, tri,tetra and penta hydrates, etc, may be employed in the docetaxelnanodispersion formulations. In certain embodiments, the docetaxel isanhydrous docetaxel. In other embodiments, the docetaxel is docetaxeltrihydrate.

Nanodispersion formulations include an effective amount of docetaxel. Byeffective amount is meant a dosage sufficient to provide the desiredresult, e.g., inhibition of cellular proliferation. The effective amountof docetaxel may range from about 0.1 to about 5 wt %, or from about 0.5to about 5 wt % (weight percent), or from about 0.5 to about 3 wt %, orfrom about 1 to about 3 wt %, or is about 2 wt %. Therefore, in certainembodiments, anhydrous docetaxel or docetaxel trihydrate is present inthe nanodispersion formulation in an amount ranging from about 0.1 toabout 5 wt %, or from about 0.5 to about 5 wt %, or from about 0.5 toabout 3 wt %, or from about 1 to about 3 wt %, or is about 2 wt %. Theconcentration of the taxane in the formulations may vary, and is in someembodiments, about 30 mg/ml or less, about 25 mg/ml or less, about 20mg/ml or less, about 10 mg/ml or less, about 1 mg/ml or less, or rangesfrom about 0.05 to about 20 mg/ml, from about 0.5 to about 20 mg/ml,from about 1 to about 20 mg/ml, or from about 5 to about 20 mg/ml.

As used herein, the term “non-aqueous” is intended to refer toformulations having a water content about 3% by weight or less. Thewater content may come from any one or more of the components in theformulation, such as the organic acid component or from the waterassociated with docetaxel trihydrate, when used. In some embodiments,the formulations comprise less than about 3% water by weight, or lessthan about 2.5% water by weight, or less than about 2% water by weight,or less than about 1.5% water by weight, or less than about 1% water byweight, or less than about 0.5% water by weight, or less than about 0.1%water by weight, or less than about 0.01% water by weight, or than about0.005% water by weight.

Also present in the nanodispersion formulations is an oil component madeup of one or more oils. Without wishing to be bound by any one theory,it is contemplated that the inclusion of the oil in the nanodispersionformulations helps stabilize the diluted solution. Oils of interest arephysiologically acceptable and include, but are not limited to: simplelipids, derived lipids, complex lipids that are derived from vegetableoil and fat, animal oil and fat, and mineral oil, or mixtures thereof,where the oils may be naturally occurring or synthetic.

In certain embodiments, the oil includes, but is not limited tovegetable oil such as soybean oil, olive oil, sesame oil, castor oil,corn oil, peanut oil, safflower oil, grape seed oil and eucalyptus oil,medium-chain fatty acid esters, low-chain fatty acid esters,triglycerides, and the like. Animal oils and fat of interest include,but are not limited to, cod-liver oil, seal oil, sardine oil,docosahexiaenoic acid, and eicosapentaenoic acid. One or a combinationof more than one of these types of oils can be used. For example, someembodiments of the subject formulations include soybean oil, olive oil,sesame oil, or combinations thereof. Other embodiments include soybeanoil, olive oil, or combinations thereof. Highly refined oils and fatscan be employed in certain embodiments. In some embodiments, the oil issoybean oil.

Oils to be used in the formulations disclosed herein may also includepolyol esters of medium chain fatty acids. The term “polyol esters ofmedium chain fatty acids” is intended to include esters and mixed estersof glycerol, propylene glycol or other open chain polyols such aspolyethylene glycol, reacted with medium chain fatty acids, e.g., wherethe acid has a chain length between 6 and 12 carbon atoms. In someinstances, the polyol esters of medium chain fatty acids aretriglycerides or diglycerides of the C₈-C₁₀ fatty acids, e.g., as may becommercially available from the fractionation of coconut oil.Commercially available products of this description are sold under thetrade names “NEOBEE®”, “ODO®”, “Panacet®”, “Miglyol®” and “Captex® 300”and have a majority of C₈ fatty acid (caprylic) triglyceride and C₁₀fatty acid (capric) triglyceride with minor levels of C₆ and C₁₄ fattyacid triglycerides. In some embodiments, the oil is NEOBEE®.

In certain embodiments, the oil is about 20 wt % or less of theformulation. In some instances, the amount of oil in the nanodispersionformulation ranges from about 0.5 to about 20 wt %, or from about 1 toabout 20 wt %, or from about 1 to about 10 wt %. In certain embodiments,the oil is present in an amount ranging from about 1 to about 5 wt %. Inother embodiments, the oil is present in an amount ranging from about 1to about 3 wt %, or about 2 wt %. In certain embodiments, the amount ofoil in the nanodispersion formulation is calculated based on the amountof docetaxel in the formulation. For example, in some embodiments, whenthe amount of oil greatly exceeds the amount of docetaxel (w/w), theparticle size can become larger, which typically results in theformulation becoming cloudy. Accordingly, in some embodiments, theamount of oil is less than about three times the amount of docetaxel(w/w), or equal to or less than about 2.5 times the amount of docetaxel(w/w), or equal to or less than about 2 times the amount of docetaxel(w/w), or equal to or less than about 1.5 time the amount of docetaxel(w/w), or is about equal to the amount of docetaxel (w/w), or is abouthalf of the amount of docetaxel (w/w).

Also present in the nanodispersion formulations is a non-ionicsurfactant, which may include one or more non-ionic surfactants.Surfactants of interest include any type of non-ionic surfactant thatcan be used for pharmaceutical formulations. Non-ionic surfactants ofinterest include, but are not limited to, polyoxyalkylene copolymer, andsorbitan fatty acid esters. In some embodiments, the sorbitan fatty acidester is a polyoxyethylene sorbitan fatty acid ester (e.g.,polyoxyethylene sorbitan tristearate (Tween® 65); polyoxyethylenesorbitan trioleate (Tween® 85); polyethylene glycol 400 monostearate;polysorbate 60; (Tween® 60); polyoxyethylene monostearate (Myrj® 49);polysorbate 80 (Tween® 80); polysorbate 40 (Tween® 40); and polysorbate20 (Tween 20)) or sorbitan fatty acid esters (e.g., sorbitan trioleate(Span® 85); sorbitan tristearate (Span® 65); sorbitan sesquioleate(Arlacel® 83); glyceryl monostearate; sorbitan monooleate (Span® 80);sorbitan monostearate (Span® 60); sorbitan monopalmitate (Span® 40); andsorbitan monolaurate (Span® 20)). In some embodiments, the non-ionicsurfactant is polysorbate 80. In some embodiments, the polysorbate 80 isrefined grade.

The amount of non-ionic surfactant in the nanodispersion formulation mayvary. In some instances, the amount of non-ionic surfactant in thenanodispersion formulation is about 40 wt % or more. In some instances,the non-ionic surfactant is present in an amount ranging from about 40to about 75 wt %, or from about 50 to about 65 wt %, or from about 50 toabout 60 wt %, or from about 50 to about 57 wt %, or from about 57 toabout 65 wt %. The combination ratio by weight of the oil and thesurfactant in the subject nanodispersion formulations may vary, and isin some instances about 1/100, or about 1/50, or about 1/40, or about1/30, or about 1/20, or about 1/10, or about 1/8, or about 1/6, or about1/4, or about 1/2, or about 1/1.

In some instances, nanodispersion formulations of the invention furtherinclude a non-aqueous solvent, which may include one or more non-aqueoussolvents. Non-aqueous solvents of interest include, but are not limitedto, propylene glycol, polypropylene glycol, polyethylene glycol (such asPEG 300, PEG 400, PEG 600, PEG 800, PEG 1000, etc., where in certainembodiments polyethylene glycols, when employed, have an averagemolecular weight of 1000 or less), glycerin, triacetin, dimethylisosorbide, glycofurol, propylene carbonate, dimethyl acetamide or amixture thereof. In some embodiments, the non-aqueous solvent ispolyethylene glycol. In some embodiments, the non-aqueous solvent ispolyethylene glycol 400. In some embodiments, the polyethylene glycolhas a melting point of less than 0° C. In some embodiments, thenon-aqueous solvent is polyethylene glycol 300.

The non-aqueous solvent may be present in varying amounts, and in someinstances is present in an amount ranging from about 20 to about 60 wt%, or from about 35 to about 45 wt %, including amounts ranging fromabout 35 to about 40 wt %, or from about 40 to about 45 wt %. Thecombination ratio by weight of the oil and the non-aqueous solvent inthe nanodispersion formulations may vary, and in some instances is about1/100, or about 1/50, or about 1/40, or about 1/30, or about 1/20, orabout 1/10, or about 1/7, or about 1/5, or about 1/3, or about 1/1.

In some instances, the amount of non-aqueous solvent is determined basedon the amount of non-ionic surfactant in the formulation. In such cases,the amount of non-ionic surfactant (w/w) should be about equal to orgreater than the amount of non-aqueous solvent (w/w) in the formulation,or greater than about 95% of the amount of non-aqueous solvent (w/w), orin other words, the ratio by weight of the non-ionic surfactant and thenon-aqueous solvent is about 0.95 or more. As is shown in the Examples,when used in such amounts, the stability of the formulation is enhanced.

The nanodispersion formulations disclosed herein further comprise anorganic acid component. The organic acid as used herein is soluble inthe non-aqueous, ethanol-free formulation (in the amount used) and doesnot contain any significant amount of (i.e., is substantially-free of)its conjugate base (or salt thereof). In some embodiments, the organicacid contains less than about 5% of its conjugate base (or saltthereof), or less than about 4%, or less than about 3%, or less thanabout 2%, or less than about 1%, or less than about 0.5%, or less thanabout 0.1%, or less than about 0.05%, or less than about 0.01%. Organicacids of interest upon which the organic acid component may be basedinclude lactic acid, succinic acid, malic acid, tartaric acid and aceticacid. In some embodiments, the nanodispersion formulations disclosedherein do not contain a buffer or a mineral acid. In some embodiments,the organic acid component is lactic acid. The lactic acid can be D- orL-lactic acid, or a mixture thereof.

The organic acid may be present in varying amounts, and in someinstances is present in an amount ranging from about 0.3 to about 3 wt%, or from about 0.3 to about 1 wt %, or from about 0.3 to about 0.6 wt%, or from about 0.4 to about 0.5 wt %, or from about 0.5 to about 1 wt%, or from about 0.7 to about 1 wt %, or about 0.8 wt %.

In some embodiments, the present disclosure provides for a non-aqueous,ethanol-free docetaxel liquid nanodispersion formulation comprising:docetaxel, soybean oil in an amount ranging from about 1 to about 5 wt%, polysorbate 80 in an amount ranging from about 50 to about 60 wt %,polyethylene glycol in an amount ranging from about 35 to about 45 wt %,and lactic acid in an amount ranging from about 0.3 to about 1% w/w andwherein said lactic acid is substantially lactate-free.

In another embodiment, the present disclosure provides for anon-aqueous, ethanol-free docetaxel liquid nanodispersion formulationcomprising: docetaxel, a medium chain triglyceride in an amount rangingfrom about 1 to about 5 wt %, polysorbate 80 in an amount ranging fromabout 50 to about 60 wt %, polyethylene glycol in an amount ranging fromabout 35 to about 45 wt %, and lactic acid in an amount ranging fromabout 0.3 to about 1% w/w and wherein said lactic acid is substantiallylactate-free.

The nanodispersion formulation typically has a pH of less than about3.5, or less than about 3.4, or less than about 3.3, or less than about3.25, or less than about 3.2, or less than about 3.1, or from about 3.0to about 3.1.

Methods of Preparing Docetaxel Nanodispersion Formulations

Nanodispersion formulations may be prepared according to any convenientprotocol. As such, the components of the desired nanodispersion may becombined under conditions sufficient to produce the desirednanodispersion. Accordingly, an amount of docetaxel, an oil, a non-ionicsurfactant, a non-aqueous solvent and an organic acid, wherein saidorganic acid is soluble in the non-aqueous solvent and is substantiallyfree of any conjugate base, may be combined under conditions sufficientto produce a nanodispersion. The components may be combined in anyconvenient order. The components may be combined at any convenienttemperature, e.g., room temperature or elevated temperatures, such astemperatures ranging from about 30 to about 95° C., about 50 to about60° C., or about 70 to about 80° C. Certain of the components may becombined with each other, and then combined together, or all of thecomponents may be combined at substantially the same time. Combinationmay include various manners of agitation or mixing, e.g., stirring,sonication, etc., in order to produce the desired nanodispersion.

As indicated above, an initial nanodispersion is prepared that includesdocetaxel, an oil, a non-ionic surfactant, a non-aqueous solvent and anorganic acid, wherein said organic acid is soluble in the non-aqueoussolvent and is substantially free of any conjugate base. In certainembodiments, the initial nanodispersion is clear. By clear is meant thatthe nanodispersion is a translucent, if not transparent liquid, i.e.,the liquid is pellucid. As such, the initial preparation is not cloudy.Further details regarding the nanodispersions that may be prepared fromthe docetaxel initial composition precursors are provided below.

In some embodiments, the present disclosure provides a method for makingthe non-aqueous, ethanol-free docetaxel nanodispersion formulation asdisclosed herein, the method comprising combining docetaxel, an oil, anon-ionic surfactant, a non-aqueous solvent and an organic acid; andsterilizing the product thereof to provide the non-aqueous, ethanol-freedocetaxel nanodispersion formulation.

The preparation methods can be carried out at certain temperature suchas temperatures ranging from about 30° C. to about 95° C., about 50° C.to about 60° C., about 60° C. to about 70° C., or about 70° C. to about80° C. Specific examples are provided in the Experimental section,below.

In some embodiments, the method for making the non-aqueous, ethanol-freedocetaxel nanodispersion formulation as disclosed herein does notcomprise the addition of water and/or ethanol, followed by removalthereof. Accordingly, since the non-aqueous, ethanol-free docetaxelnanodispersion formulation has not been contacted with either water orethanol during the formulation process, it is substantially free ofwater (i.e, less than about 3%) and free of ethanol. In someembodiments, the formulation is essentially free of water (i.e, lessthan about 1%). In addition, in certain embodiments, the formulations donot have any detectable amount of ethanol. This results in a formulationwhich is stable and can be suitable for subjects having an adversereaction to ethanol. In some embodiments, the formulations do notcontain activated carbon.

Where desired, an amount of the nanodispersion may be loaded into anindividual dosage container, e.g., vial, which holds the nanodispersionand keeps it sterile during shipping, storage, and handling. Before orduring the loading stage, the nanodispersion can be passed through asub-micron sterilizing filter, e.g., a 0.2 μm hydrophilic filter) whichhas a sufficiently small pore size to remove any bacteria or viruses.The sterilizing filters of interest include, but are not limited tohydrophilic filters. In some embodiments, the filter could be a CA(Cellulose Acetate) membrane filter, PTFE (Polytetrafluoroethylene)membrane filter, PVDF (Polyvinylidene fluoride or polyvinylidenedifluoride) membrane filter or PES (Polyethersulfone) membrane filter.

As used herein, the term “vial” refers to any container that is used tohold the nanodispersion formulation. Many pharmaceutical vials are madeof clear glass, which allows several advantages, including visualinspection of the enclosed drug (to ensure that it is still in a clean,non-caramelized, non-collapsed form, when it is ready for use) and ofthe container itself (to ensure that it does not have a hairline crackin one of the walls, which could jeopardize or destroy sterility of theenclosed drug). Various types of pharmaceutical vials are known.Single-chamber vials can be sealed with rubber or plastic plugs thatwill allow a hypodermic needle to be pushed through the rubber seal.Examples include any hydrolytically stable glass, such as a borosilicateType I or soda-lime-silica Type II glass vial, having a suitable stopper(e.g., Teflon coating). Alternately, a single-chamber vial can be madeof a brittle and easily breakable material, inside a sealed bag that cancontain an aqueous solution (such as physiological saline or a dextrosesolution, in an intravenous infusion bag); if this type of vial isbroken, it will release its contents into the still-sealed bag, formixing. In yet other embodiments, two-chamber vials or analogousstructures, e.g., as described in Published United States ApplicationPublication No. 2003/0099674 and U.S. Pat. No. 4,781,354 may beemployed. Other methods for preparing the docetaxel formulationsdisclosed herein can be found in Published United States ApplicationPublication No. 2011/0269829, the entirety of which is incorporatedherein by reference.

Docetaxel Formulations and Methods of Use

Following preparation of the nanodispersion formulation, e.g., asdescribed above, at the time of desired administration to a subject, adosage amount of the nanodispersion may be combined with an aqueousmedium to prepare a docetaxel diluted solution that is suitable for use.The dosage amount of the nanodispersion formulation may be combined withany suitable aqueous medium, where aqueous mediums of interest include,but are not limited to: deionized water, USP water for injection (WFI),salines, transfusion solutions, physiological solutions, etc. In someembodiments, the aqueous medium comprises an aqueous 0.9% sodiumchloride solution or an aqueous 5% dextrose solution. The liquids tonanodispersion (high viscous liquid) ratio employed during preparationof the diluted solution may vary, and in certain embodiments ranges from0.5 to 300, such as 1 to 100, 2 to 50 or 2 to 20, and including 2 to 10.In some instances, the dosage amount of nanodispersion formulation thatis combined with the aqueous medium ranges from 100 to 1200 g, such as300 to 600 g and the amount of aqueous medium that is combined with thedosage amount ranges from 100 to 1200 ml, such as 250 to 600 ml.

The docetaxel diluted solutions prepared from the nanodispersionformulations are liquid preparations that are a suspension of smallparticles (i.e., globules) of one liquid in a second liquid with whichthe first liquid will not mix. The water present in the docetaxeldiluted solutions may be any convenient water, including deionizedwater, USP water for injection (WFI), etc.

The docetaxel diluted solutions include docetaxel, an oil, a non-ionicsurfactant, a non-aqueous solvent and an organic acid, wherein saidorganic acid is soluble in the non-aqueous solvent and is substantiallyfree of any conjugate base, and an aqueous medium. In certainembodiments, the docetaxel diluted solutions are clear. By clear ismeant that the diluted solution is a translucent, if not transparentliquid, i.e., the liquid is pellucid. As such, the diluted solution isnot cloudy, e.g., as a suspension may appear. Further details regardingthe docetaxel diluted solutions that may be prepared from the docetaxelnanodispersion precursors are provided below. In some instances, theparticle size of the final docetaxel diluted solutions ranges from about3 to about 70 nm, such as about 5 to about 50 nm and including about 7to about 30 nm, such as about 8 to about 15 nm. In some instances, anydifference in particle size between the non-aqueous formulation and thedocetaxel diluted solution is minimal, such that the particle sizes inthe non-aqueous formulation and the docetaxel diluted solution aresubstantially the same. In some instances, any difference in particlesize between the non-aqueous formulation and the docetaxel dilutedsolution is about 30 nm or less, such as about 20 nm or less, about 15nm or less, about 10 nm or less, or about 5 nm or less. Without wishingto be bound by any one theory, it is contemplated that the inclusion ofthe oil in the nanodispersion formulations helps stabilize the dilutedsolution.

Where desired, the nanodispersion formulation may be stored for a periodof time prior to combination with the aqueous medium. This storage timeof the nanodispersion composition may vary, where storage times may beabout 1 year or more, such as about 2 years or more, including about 3years or more. While the storage conditions may vary, in certaininstances the storage conditions are characterized by a temperatureranging from about 5 to about 60° C., e.g., about 5° C., such as about 8to about 40° C., e.g., about 25° C. The activity of the docetaxel issubstantially preserved during the storage period, such that thenanodispersion formulations are storage stable. As such, the activity ofthe docetaxel in the docetaxel diluted solution following storage issubstantially the same as that in the nanodispersion prior to beingcombined with an aqueous medium, where the magnitude of any differencein activity between the non-aqueous formulation and the docetaxeldiluted solution may be about 15% or less, such as about 10% or less,including about 5% or less.

As shown in Example 2, the nanodispersion formulation according thepresent disclosure is stable for more than about 3 months at about 40°C., or is stable for more than about 6 months at about 40° C. (seeExample 3). In contrast, the formulations which contain lactic acidbuffer (i.e., lactic acid with sodium lactate) rather than lactic acidalone show signs of deterioration during the same time period. Thestability of the present nanodispersion formulations can be determinedby methods known in the art, such as by measuring the percentdeterioration of the docetaxel peak by HPLC or by measuring recoveryrate for the docetaxel by HPLC. In some embodiments, the nanodispersionformulation exhibits a docetaxel recovery rate of more than about 95%after 6 months at about 40° C., or about 96% or more, or more than about97% or more, or more than about 98% or more, or about 99% or more. Therecovery rate is calculated based on the measured amount of docetaxel inthe formulation, which is not necessarily the amount of docetaxel addedto the formulation (thus eliminating any potential error from animpurity in the docetaxel).

The docetaxel diluted solutions that are produced upon dilution of thenanodispersion formulation with the aqueous medium can have aphysiologically acceptable pH. In certain embodiments, the pH of thediluted solutions ranges from about 2.5 to about 8, such as from about 3to about 7, including from about 3.5 to about 6. The docetaxel dilutedsolutions are clear (i.e., transparent) formulations. The concentrationof docetaxel in the diluted solution may vary, ranging in someembodiments from about 0.05 to about 10 mg/ml, such as about 0.2 toabout 3 mg/ml.

The combination protocol may vary, where agitation may be employed,e.g., by stirring, by kneading a bag that includes both thenanodispersion formulation and the aqueous medium.

Methods of using the docetaxel diluted solutions include administeringan effective amount of the docetaxel diluted solution to a subject inorder to treat the subject for a target condition of interest. By“treating” or “treatment” is meant at least a suppression or anamelioration of the symptoms associated with the condition afflictingthe subject, where suppression and amelioration are used in a broadsense to refer to at least a reduction in the magnitude of a parameter,e.g., symptom, associated with the condition being treated, such aspain. As such, treatment also includes situations where the condition iscompletely inhibited, e.g., prevented from happening, or stopped, e.g.,terminated, such that the subject no longer experiences the condition.As such, treatment includes both preventing and managing a condition.

In practicing the methods, the diluted solutions disclosed herein can beparenterally administered to a subject. By “parenteral administration”is meant administration by a protocol that delivers a quantity of thediluted solutions to the subject, e.g., a patient suffering from acellular proliferative disease, by a route other than the digestivetract. Examples of parenteral administration include, but are notlimited to, intramuscular injection, intravenous injection, and thelike. In certain embodiments, parenteral administration is by injectionusing an injection delivery device. The amount of diluted solutions thatis administered to the subject may vary depending on a number offactors, such as patient specifics, nature of condition, etc.

In certain embodiments, the subject methods include a diagnostic step.Individuals may be diagnosed as being in need of the subject methodsusing any convenient protocol. In addition, individuals may be known tobe in need of the subject methods, e.g., they are suffering from atarget disease condition (e.g., cellular proliferative disease, prior topracticing the subject methods). Diagnosis or assessment of targetcondition can be performed using any convenient diagnostic protocol.

Methods of the invention may further include assessing the efficacy ofthe treatment protocol that includes administration of the docetaxeldiluted solution. Assessing the efficacy of treatment may be performedusing any convenient protocol.

The docetaxel diluted solutions of the invention may be administered toa variety of different types of subjects. Subjects of interest include,but are not limited to: mammals, both human and non-human, including theorders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guineapigs, and rats), lagomorpha (e.g., rabbits) and primates (e.g., humans,chimpanzees, and monkeys). In certain embodiments, the subjects, e.g.,patients, are humans.

Accordingly, provided herein are methods of administering anethanol-free docetaxel liquid nanodispersion formulation to a subject,the method comprising: (a) combining the ethanol-free docetaxelnanodispersion formulation according to the present disclosure with anaqueous medium to provide an ethanol-free docetaxel diluted solution;and (b) administering the ethanol-free docetaxel diluted solution to thesubject.

In some embodiments, the method of using the docetaxel nanodispersionformulation comprises the steps of: (a) aseptically withdrawing thedesired amount of the docetaxel nanodispersion formulation (such as aformulation comprising about 20 mg docetaxel/mL) with a calibratedsyringe, (b) injecting said formulation into a 250 mL infusion bag orbottle of either 0.9% sodium chloride solution or 5% dextrose solutionto provide a diluted solution having a final docetaxel concentration offrom about 0.3 mg/mL to about 0.74 mg/mL, and (c) administering saiddiluted solution to a patient. If a dose greater than 200 mg ofdocetaxel is required, one may use a larger volume of the infusionvehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded.

In certain embodiments, the volume of diluted solution that isadministered to a subject may range from about 100 to about 1000 ml,such as about 200 to about 600 ml. The time period over which thisvolume is administered may vary, ranging from about 0.5 to about 6 hr,such as from about 1 to about 3 hr. Dosages administered to a subjectduring a given procedure may also vary, ranging in some instances fromabout 20 to about 500 mg/m², such as from about 50 to about 300 mg/m².

In determining whether to administer the diluted solution to aparticular given subject, care will be taken to ensure that theformulation is not contraindicated for that subject. As such, symptomsof the subject may be assessed to ensure that administration of thediluted solution will not have adverse effects that outweigh any benefitthat the diluted solution may provide.

Utility

The subject diluted solutions and methods find use in a variety ofapplications, including the treatment of subjects suffering fromcellular proliferative disease conditions. Cellular proliferativediseases that may be treated with formulations of the invention include,but are not limited to: carcinomas, myelomas, neuroblastomas, orsarcomas, of the brain, breast, lung, colon, prostate or ovaries, aswell as leukemias or lymphomas. Specific disease conditions of interestinclude, but are not limited to, human ovarian cancer, breast cancer,malignant lymphoma, lung cancer, melanoma, and Kaposi's sarcoma.

Kits

Also provided are kits that find use in practicing the subject methods,as described above. For example, kits for practicing the subject methodsmay include a quantity of the nanodispersion formulation, present inunit dosages, e.g., vials, or a multi-dosage format. As such, in certainembodiments, the kits may include one or more unit dosages (e.g., vials)of the nanodispersion formulation. The term “unit dosage”, as usedherein, refers to physically discrete units suitable as unitary dosagesfor human and animal subjects, each unit containing a predeterminedquantity of the subject nanodispersion formulation calculated in anamount sufficient to produce the desired effect. The amount of the unitdosage of the subject formulation depends on various factors, such asthe particular active agent employed, the effect to be achieved, and thepharmacodynamics associated with the active agent in the subject. In yetother embodiments, the kits may include a single multi-dosage amount ofthe formulation.

In certain embodiments, the kits may further include an amount of anaqueous medium suitable for use in production of the docetaxel dilutedsolution. The aqueous medium may be any convenient aqueous medium, suchas described above, present in any suitable container, e.g., an IV bag.

In some embodiments, the kits may include a syringe which is suitable toprepare the docetaxel diluted solution. A syringe with graduations ispreferred to measure a certain amount of the docetaxel nanodispersion.

In addition to the above components, the subject kits may furtherinclude instructions for practicing the subject methods. Theseinstructions may be present in the subject kits in a variety of forms,one or more of which may be present in the kit. One form in which theseinstructions may be present is as printed information on a suitablemedium or substrate, e.g., one or more pieces of paper on which theinformation is printed, in the packaging of the kit, in a packageinsert, etc. The instructions may be present on a computer readablemedium, e.g., diskette, CD, DVD, etc., on which the information has beenrecorded. The instructions may be present on a website, which may beused via the internet to access the information at a removed site. Otherconvenient means are possible and may be included in the kits.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

EXPERIMENTAL Example 1 General Formulation Nanodispersion Formulation

Taxane (e.g., anhydrous docetaxel or docetaxel trihydrate), oil (e.g.,soybean oil), surfactant (e.g., polysorbate 80), non-aqueous solvent(e.g., polyethylene glycol 300, average molecule weight=300) and organicacid component (e.g., lactic acid or lactic acid mixture of 4:1 by wtlactic acid to sodium lactate) are placed into a beaker. The beaker isheated to 70-80° C. and the ingredients mixed via ultrasonic dispersion.

The resultant solution is poured into a vial through a 0.2 micron filterwhile applying nitrogen and the tube sealed. Optionally, steam treatment(95° C.×30 min.) can then be applied.

Diluted Solution

The resultant nanodispersion formulation is then placed into a testtube. Purified water was added and the tube was shaken by hand for about20 seconds to obtain a clear solution. The particle size is thenmeasured via a particle size distribution in the dynamic lightscattering measurement protocol.

The various studies performed using nanodispersion formulations anddiluted solutions prepared as described above are outlined in theExamples below.

Example 2 Oil Studies

Nanodispersion samples were prepared according to Example 1 and 0.5 mlof the sample was added to 25 ml of 5% glucose solution in a glasscentrifuge tube. The tube was shaken by hand for about 20 seconds. Thediluted sample was evaluated by visual inspection for phase separation,color, clarity, consistency and particulates in the clear, glass tube.

Oil Study 1

In the following Example, all components were mixed, water was added,and the formulation was autoclaved then left at room temperature forfour days. As shown in Table 1, when the ratio of soybean oil todocetaxel (by weight) is 1 (Entry (1)) or 2.5 (Entry (2)), there was nophase separation observed after 4 days.

TABLE 1 Formulation A (1) (2) Docetaxel 4 4 Soybean oil 4 10 Polysorbate80 (GS) 100 100 Polyglycol (PG) 90 90 Glycerin 10 10 LA-Buffer (8:2) 1 1Physical appearance ∘ ∘ of the dispersion sample (4 days later) ∘: Clearand free from particle matter Δ: Very slightly cloudy x: Slightlycloudy/cloudy/phase separation/precipitation

Oil Study 2

As shown in Table 2, when the ratio of soybean oil to docetaxel (byweight) is three (Entry (2)), the quality of the nanodispersiondeclines.

TABLE 2 Formulation B (1) (2) Docetaxel trihydrate 4 4 MCT (NEOBEE 1053)8 12 Polysorbate 80 (TO-10MV) 95 95 Lactic Acid Buffer 1 1 (LA: 70% LANa= 8:2) PEG 300 (MG300) 70 70 Physical appearance of ∘ x* dispersion ∘:Clear and free from particle matter Δ: Very slightly cloudy x: Slightlycloudy/cloudy/phase separation/precipitation *gelatinous look

Oil Study 3

The following docetaxel nanodispersion solutions were evaluated byvisual inspection for phase separation, color, clarity, consistency andparticulates in clear, glass tubes when they were prepared. In addition,5.25 ml of each sample was combined with 250 ml of 0.9% sodium chloridesolution or 5% glucose solution. The diluted solution was then visuallyinspected after 6 hours and 24 hours. The results are shown in Tables 3and 4. The stability of the docetaxel diluted solution was increased byadding oil.

TABLE 3 Formulation C (1) (2) (3) (4) Docetaxel 4 4 4 4 MCT (NEOBEE1053) 0 0 4 4 Polysorbate 80 (TO-10MV) 100 100 100 100 PEG 300 (MG300)40 40 40 40 PEG 400 (MG400) 10 60 10 60 Lactic Acid Buffer 1 1 1 1Physical appearance of ∘ ∘ ∘ ∘ dispersion (0 days) Physical appearanceof ∘~Δ ∘~Δ ∘ ∘ diluted solution (6 hrs) Physical appearance of x x Δ Δdiluted solution (24 hrs) ∘: Clear and free from particle matter Δ: Veryslightly cloudy x: Slightly cloudy/cloudy/phase separation/precipitation

TABLE 4 Formulation D (1) (4) Docetaxel trihyrate 4 4 Soybean oil 0 4Polysorbate 80 (TO-10MV) 95 95 Lactic Acid Buffer 1 1 LA: 70% LANa =8:2) PEG 300 (MG300) 70 70 Physical appearance of x x ∘ Δ dilutedsolution (6 hrs) ∘: Clear and free from particle matter Δ: Very slightlycloudy x: Slightly cloudy/cloudy/phase separation/precipitation

Oil Study 4 Comparison Example

Table 5 shows the stability of formulations provided using water in theformulation process (see US2011/0269829, section II: DocetaxelFormulations, A. Working example 1.). Particle size was measured beforethe water removal process.

TABLE 5 Formulation E Formulation E Formulation F Formulation F (1) (3)(1) (3) Docetaxel  4 (200 mg)  4 (200 mg)  4 (200 mg)  4 (200 mg)Soybean oil  10 (500 mg)  4 (200 mg) — — MCT* — —  10 (500 mg)  4 (200mg) Polysorbate 80 100 (5 g) 100 (5 g) 100 (5 g) 100 (5 g) PG 100 (5 g)100 (5 g) 100 (5 g) 100 (5 g) Lactic Acid Buffer  5  5  5  5 (LA 155 mg,70% LANa 95 mg) Particle size (nm) 17.5 (wide) 12.8 14.7 (wide) 12.1Physical appearance Cloudy, phase Transparent, Transparent, Transparent,of dispersion after separation clear clear clear water removal (0 days)*MCT: Nisshin O.D.O

Example 3 PEG (Polyethylene Glycol)

Nanodispersion samples were prepared according to Example 1 andevaluated by visual inspection for phase separation, color, clarity,consistency and particulates in clear, glass vials.

PEG Study 1: Stability

The formulations shown in Table 6 were stored at 40° C./75% RH for 6months (Formulation G, Entries (1), (2), and (3)) and 5° C. for 6 months(Formulation H, Entries (1), (2), and (3)). Table 6 shows that theformulations which used PEG 300, which has a melting point of −15° C. to−8° C., maintained transparency.

TABLE 6 Formulation G Formulation H (1) (2) (3) (1) (2) (3) Docetaxeltrihydrate  4 mg  4 mg MCT (NEOBEE 1053)  4  4 Polysorbate 80 (TO- 95 9510MV) PEG 300 (MG300) 70 — PEG 400 (MG400) — 70 LA-Buffer  1  1 (LA: 70%LANa = 8:2) Physical appearance of (1) (2) (3) (1)Yellow/Transparent/Clear dispersion after 6 Yellow/Transparent/Clear (2)(3) months at 40° C. Yellow/Transparent/Slightly cloudy Physicalappearance of (1) (2) (3) (1) (2) (3) dispersion after 6 Yellow andcloudy. Yellow and cloudy. months at 5° C. Floating subjects observedFloating subjects were seen when temperature was still when thetemperature was still low. low. When the temperature was When thetemperature was back to room temperature, it back to room temperature,it was Yellow/Transparent/Clear. was Yellow/Transparent but still Cloudyand Ununiform.

PEG Study 2: Solubility

Formulations of anhydrous docetaxel and either PEG 400 or PEG 300 wereprepared and mixed using ultrasonic dispersion for 5 minutes at 70-80°C. 1 g of PEG 400 dissolved 25 mg of anhydrous docetaxel. 1 g of PEG 400did not fully dissolve 50 mg of anhydrous docetaxel. 1 g of PEG 300dissolved 100 mg of anhydrous docetaxel. Accordingly, PEG 300 was ableto better solubilize anhydrous docetaxel.

PEG Study 3: Polysorbate/PEG Ratio

As shown in Table 7, when the ratio of polysorbate to PEG is greaterthan or equal to 1 (i.e., the amount of polysorbate is greater than orequal to the amount of PEG), the formulations exhibit stability comparedto formulations having less PEG with respect to polysorbate.

TABLE 7 Formulation Formulation Formulation Formulation FormulationFormulation C (4) C (5) C (6) I (4) I (5) I (6) Docetaxel 4 4 4Docetaxel trihydrate 4 4 4 MCT (NEOBEE 4 4 4 4 4 4 1053) Polysorbate 80(TO- 100 100 100 95 95 95 10MV) PEG300 (MG300) 40 40 20 100 50 0 PEG400(MG400) 10 60 80 0 50 100 LA-Buffer 1 1 1 1 1 1 Total 159 209 209 204204 204 Ratio 2 1 1 0.95 0.95 0.95 Polysorbate/PEG Physical appearance ∘∘ ∘ x Slightly x Slightly ∘ of dispersion after 0 cloudy Cloudy dayPhysical appearance ∘ x phase x phase x phase x phase x phase ofdispersion after 1 separation separation separation separationseparation day slightly Physical appearance x x x phase of dispersionafter 6 separation days ∘: Clear and free from particle matter Δ: Veryslightly cloudy x: Slightly cloudy cloudy/phase separation/precipitation

PEG Study 4: Polysorbate/PEG Ratio (No API)

In Tables 8, 9 and 10, when the ratio of polysorbate to PEG is greaterthan or equal to 0.95 or 1 (i.e., the amount of polysorbate is greaterthan or about equal to the amount of PEG), the formulations exhibitstability compared to formulations having more PEG with respect topolysorbate (no taxane was added in Tables 8 and 9).

TABLE 8 Formulation J (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) Ratio 2 10.95 0.8 0.33 1.33 4 Polysorbate/PEG Polysorbate 80 (TO- 100 100 100 9595 95 8 8 80 80 10MV) PEG 300 (MG300) 40 40 20 100 50 0 10 24 0 0 PEG400 (MG400) 10 60 80 0 50 100 0 0 60 20 Physical appearance ∘ ∘ ∘ ∘ ∘ Δx x ∘ ∘ of dispersion after 0 day Physical appearance ∘ ∘ ∘ x x x x x ∘∘ of dispersion after 5 days ∘: Clear and free from particle matter Δ:Very slightly cloudy x: Slightly cloudy/cloudy/phaseseparation/precipitation

TABLE 9 Formulation K 1 2 3 4 5 6 7 8 9 10 11 Ratio 0.33 0.67 1Polysorbate/ PEG PEG 300/400 0/100 25/75 50/50 75/25 100/0 0/100 25/7550/50 75/25 100/0 75/25 (MG300/400) Polysorbate 80 8 8 8 8 8 16 16 16 1616 16 (TO-10MV) PEG 300 0 6 12 18 24 0 6 12 18 24 12 (MG300) PEG 400 2418 12 6 0 24 18 12 6 0 4 (MG400) Physical x x x x x x x x x x ∘appearance of dispersion after 0 day ∘: Clear and free from particlematter Δ: Very slightly cloudy x: Slightly cloudy/cloudy/phaseseparation/precipitation

TABLE 10 Formulation L (1) (2) (3) (4) Docetaxel trihydrate 4 4 4 4 MCT(NEOBEE 1053) 0 0 4 4 Polysorbate 80 (TO- 95 95 95 95 10MV) PEG 300(MG300) 40 85 40 85 PEG 400 (MG400) 10 0 10 0 Lactic Acid Buffer 1 1 1 1Total 150 185 154 189 Polysorbate/PEG Ratio 1.9 1.12 1.9 1.12 Physicalappearance of ∘ ∘ ∘ ∘ dispersion after 0 day Physical appearance of ∘ ∘∘ ∘ dispersion after 7 days ∘: Clear and free from particle matter Δ:Very slightly cloudy x: Slightly cloudy/cloudy/phaseseparation/precipitation

PEG Study 5: Polysorbate/PEG Ratio

Tables 11 and 12 show that the oil contributes to the stability of thedocetaxel nanodispersion.

TABLE 11 Formulation M (1) Docetaxel trihydrate 4 MCT (NEOBEE 1053) 4Polysorbate 80 (TO-10MV) 95 PEG 300 (MG300) 70 Lactic Acid Buffer 1Total 174 Polysorbate/PEG Ratio 1.36 Physical appearance of ∘ dispersionafter 5 days ∘: Clear and free from particle matter Δ: Very slightlycloudy x: Slightly cloudy/cloudy/phase separation/ precipitation

TABLE 12 Formulation N (4) (6) Docetaxel trihydrate 4 4 MCT (NEOBEE1053) 0 0 Polysorbate 80 (TO-10MV) 95 95 PEG 300 (MG300) 70 85 LacticAcid Buffer 1 1 Polysorbate/PEG Ratio 1.36 1.12 Physical appearance of ∘Δ dispersion after 0 days Physical appearance of ∘ ∘ dispersion after 1days ∘: Clear and free from particle matter Δ: Very slightly cloudy x:Slightly cloudy/cloudy/phase separation/precipitation

PEG Study 6: PEG and PG (Polyglycol) Comparison

Table 13 shows that even with a polysorbate/PG ratio greater than 1, theformulation did not satisfy the desired quality level.

TABLE 13 Formulation O (1) Docetaxel trihydrate 4 (120 mg) MCT (NEOBEE1053) 4 (120 mg) Polysorbate 80 (TO-10MV) 95 (2.85 g) Lactic Acid Buffer1 (30 mg) (LA: 70% LANa = 8:2) Polyglycol 70 70 (2.1 g)Polysorbate/Polyglycol Ratio 1.36 Physical appearance of Δ dispersionafter 0 days Physical appearance of x dispersion after 1 days ∘: Clearand free from particle matter Δ: Very slightly cloudy x: Slightlycloudy/cloudy/phase separation/precipitation

Table 14 shows that even when the polysorbate/polyglycol&PEG ratio wasover 1, when polyglycol was added, the quality of the nanodispersiondeclined.

TABLE 14 Formulation P (1) (2) Docetaxel trihydrate 4 (120 mg) 4 (120mg) MCT (NEOBEE 1053) 4 (120 mg) 4 (120 mg) Polysorbate 80 (TO-10MV) 95(2.85 g) 95 (2.85 g) Lactic Acid Buffer 1 (30 mg) 1 (30 mg) (LA: 70%LANa = 8:2) PEG 300 (MG300) 40 (1.2 g) 30 (900 mg) Polyglycol 0 40 (1.2g) Polysorbate/Polyglycol&PEG 0.42 1.36 Ratio Physical appearance ofSlightly cloudy Cloudy, Particulates dispersion after 2 days Physicalappearance of ∘, Δ (2 samples) N/A diluted solution (3 hr) ∘: Clear andfree from particle matter Δ: Very slightly cloudy x: Slightlycloudy/cloudy/phase separation/precipitation

Example 5 Buffering Agent Lactic Acid Study 1: Lactic Acid and LacticAcid Buffer

Lactic acid lowered the pH further than lactic acid buffer (docetaxel isstable at pH 3.0-4.0) (Table 15).

TABLE 15 Formulation Q (1) (2) (3) (4) Docetaxel — 4 (120 mg) — —Docetaxel trihydrate 4 (120 mg) — — — MCT (NEOBEE 1053) 4 (120 mg) 4(120 mg) 4 (200 mg) 4 (200 mg) Polysorbate 80 (TO- 95 (2.85 g) 95 (2.85g) 95 (4.75 g) 95 (4.75 g) 10MV) PEG 300 (MG300) 70 (2.1 g) 70 (2.1 g)70 (3.5 g) 70 (3.5 g) Lactic Acid Buffer — — — 1 (50 mg) (LA: 90% LANa =8:2) Lactic Acid 0.8 (24 mg) 0.8 (24 mg) 0.8 (40 mg) — Physicalappearance of ∘ two bubbles ∘ two bubbles ∘ ∘ dispersion were seen wereseen pH of diluted solution 3.19 3.16 3.15 3.43 ∘: Clear and free fromparticle matter Δ: Very slightly cloudy x: Slightly cloudy/cloudy/phaseseparation/precipitation

Example 6 Water Free Formulation

Lactic Acid Study 1: LA and LA buffer

The formulations in Tables 16 and 17 exhibit stability over a six monthperiod. In the Tables, the lactic acid formulations exhibited anenhanced stability when compared to the lactic acid buffer formulations(Table 16 vs Table 17).

TABLE 16 Formulation Formulation Formulation Formulation R S (1)(2) G(1)-(3) Formulation T U (2) Formulation V Docetaxel — — — — — 4Docetaxel 4 4 4 4 4 — trihydrate NEOBEE 1053 4 4 4 4 4 4 Polysorbate 8095 95 95 95 — — (TO-10 MV) Polysorbate 80 — — — — 95 95 (GS) PEG 300(MG300) 70 70 35 + 35 35 + 35 70 70 Lactic Acid Buffer 1 1 (100 mg) 1(100 mg) — — — (LA:70% LANa = 8:2) Lactic Acid Buffer — — — 1 — —(LA:90% LANa = 8:2) Dehydrated Lactic — — — — 0.8 0.8 Acid Buffer(LA:90% LANa = 8.4:1.6) Docetaxel recovery 86.7-89.3% 86.7-89.3%86.4-88.2% (1 month) 94.5% 91.1% rate after 6 months 95.8% Degradationpeak 3.3-3.6% 3.3-3.6% 2.6-2.9% (1 month)  1.9%  3.9% after 6 months 1.7% pH of docetaxel 3.50 3.50 3.61-3.62    (1 month) 3.55 3.54nanodispersion 3.53 pH of diluted 3.69-3.70    3.69-3.70    3.77-3.80   — — — solution

TABLE 17 Formulation W Formulation X Formulation Y Formulation Z (1)-(3)(1)-(3) (1)-(3) (1)-(3) Docetaxel 4 — 4 — Docetaxel trihydrate — 4 —4.27 NEOBEE 1053 4 4 — — Soybean oil — — 4 4 Polysorbate 80 (GS) 95 9595 95 PEG 300 (MG300) 70 70 70 70 Lactic Acid 0.8 0.8 0.8 0.8 Docetaxelrecovery rate after 96.9-98.0%   99.3-100.7% 101.6-102.3% 101.4-102.4%6M Degradation peak after 6 1.0-1.4% 0.8% 0.1% 0.1% months pH ofdocetaxel 3.07-3.10   3.01-3.02 3.02-3.06   3.05-3.11   nanodispersionpH of diluted solution — 3.54-3.57 3.54-3.57   3.54-3.57  

Example 1a Docetaxel Nanodispersion Formulations Using Lactic Acid

Docetaxel, an oil, a non-ionic surfactant, a non-aqueous solvent andlactic acid were placed into a beaker. The beaker was heated to 70-80°C., the ingredients mixed via ultrasonic dispersion, the resultantsolution was added to a vial tube through a 0.2 μm filter while applyingnitrogen and the tube was sealed.

To determine particle size, a non-aqueous composition as prepared usingthe general procedure outlined above was placed into a test tube.Purified water was added and the tube was shaken by hand for about 20seconds to obtain a clear solution. When the particle size was measuredvia a particle size distribution in the dynamic light scatteringmeasurement protocol, the average particle size was observed to bebetween about 8 and about 13 nm.

Specific formulations (in mg) as prepared via the general methoddisclosed above are summarized in Table 1a, below.

TABLE 1a Oil MCT Surfactant Solvent Docetaxel (NEOBEE ® MCT SoybeanPolysorbate PEG 300 Lactic No. Anhydrous Trihydrate #1053) (Panacet ®)Oil 80 (MG-300) Acid 1A 4 4 95 70 0.8 1B 4 4 95 70 0.8 1C 4 4 95 70 0.82A 4 4 95 70 0.8 2B 4 4 95 70 0.8 2C 4 4 95 70 0.8 3A 4 4 95 70 0.8 3B 44 95 70 0.8 4A 4.27* 4 95 70 0.8 4B 4.27* 4 95 70 0.8 4C 4.27* 4 95 700.8 5A 4 4 95 70 0.8 5B 4 4 95 70 0.8 5C 4 4 95 70 0.8 6 4 4 95 70 0.8*4.27 mg Docetaxel trihydrate is equivalent to 4 mg of docetaxel.

Example 2a Docetaxel Nanodispersion Formulations Using Lactic AcidBuffer

Docetaxel formulations were prepared according to the general procedureoutlined in Example 1a using 1 mg of lactic acid buffer (0.80 mg Lacticacid and 0.20 mg 90% sodium lactate) rather than lactic acid. Theseformulations are summarized Table 2a, below.

TABLE 2a Oil MCT Surfactant Solvent Docetaxel (NEOBEE ® Polysorbate 80Polysorbate 80 PEG 300 PEG 400 No. Anhydrous Trihydrate #1053) (refinedgrade) (TO-10MV) (MG-300)*** (MG-400)****  7* 4 4 95 70  8* 4 4 95 70 9A^(#) 4 4 95 70  9B^(#) 4 4 95 70  9C** 4 4 95 70  9D**^(#) 4 4 95 7010A^(†) 4 4 95 70 10B^(†) 4 4 95 70 10C^(†) 4 4 95 70 11A^(†) 4 4 95 7011B^(†) 4 4 95 70 11C^(†) 4 4 95 70 12A^(†) 4 4 95 70 12B^(†) 4 4 95 7012C^(†) 4 4 95 70 13^(†) 4 4 95 70 *Dehydrated 90% sodium lactate byinfrared radiation **Steam treatment (95° C. × 30 min) was applied***Average molecule weight = 300 ****Average molecule weight = 400^(†)0.80 mg Lactic acid and 0.20 mg 70% sodium lactate ^(#)0.80 mgLactic acid and 0.20 mg 90% sodium lactate

Example 3a Stability Study

The docetaxel recovery rate, percent degradation peak (as measured byHPLC) and formulation pH were measured at one month, three months andsix months at 40° C. pH was measured by mixing 3 ml of water and 750 mlof docetaxel nanodispersion sample. The results from this stabilitystudy are shown in Table 3a, below. Each formulation having lactic acidrather than either lactic acid buffer or lactic acid buffer fromdehydrated sodium lactate showed a significant increase in stability.

TABLE 3a 1 month 3 months 6 months Recovery Recovery Recovery 0 monthrate % rate % rate % Docetaxel Degradation (against 0 Degradation(against 0 Degradation (against 0 Degradation No. (mg) Peak % pH month)Peak % pH month) Peak % pH month) Peak % pH  6 3.722 None 3.12 98.3 None3.10  1A 3.570 None 3.06 100.8 None 3.04 98.0 0.20 3.03 99.3 0.8 3.01 1B 3.550 None 3.09 102.1 None 3.03 98.1 0.30 3.05 100.7 0.8 3.01(3.57*)  1C 3.570 None 3.08 101.6 None 3.03 97.9 0.30 3.04 100.5 0.83.02 (3.54*)  7 3.750 None 3.27 97.3 1.1 3.41 94.7 2.40 3.47 91.1 3.93.54  8 3.542 0.20 3.32 96.5 1.9 3.45 92.7 2.20 3.49 94.5 1.9 3.55  2A3.800 None 3.04 97.4 None 3.04 97.3 0.40 3.03 96.9 1.4 3.07 (3.63*)(3.55*)  2B 3.784 None 3.05 99.4 None 3.03 97.6 0.30 3.06 97.0 1.0 3.10(3.59*) (3.56*)  2C 3.810 None 3.04 98.1 None 3.03 98.1 0.40 3.02 98.01.1 3.07 (3.57*) (3.55*)  3A 3.805 None 3.04 97.5 None 3.05 96.8 None3.07  3B 3.635 None 3.08 97.4 None 3.05 96.8 None 3.07  9A 3.840 None3.44 95.3 2.1 3.57 90.2 2.50 3.60  9B 3.640 None 3.38 96.5 1.9 3.43 91.81.90 3.46  9C 3.670 None 3.44 95.5 1.6 3.56 88.4 3.40 3.57  9D 3.650None 3.38 96.2 1.4 3.41 87.6 4.70 3.44 10A 3.766 0.20 96.3 2.4 3.54 90.22.90 3.53 88.7 2.1 3.60 (3.77*) 10B 3.722 0.20 96.7 2.1 3.57 90.9 2.803.57 87.4 2.2 3.63 (3.78*) 10C 3.750 0.20 96.4 2.5 3.56 91.3 2.80 3.5688.2 2.2 3.62 (3.76*) 11A 3.740 0.20 96.9 2.0 3.52 91.2 3.40 3.55 86.42.9 3.61 (3.77*) 11B 3.654 0.20 97.9 1.9 3.55 91.6 3.10 3.55 88.0 2.73.61 (3.78*) 11C 3.732 0.20 97.0 2.2 3.55 90.7 3.30 3.55 88.2 2.6 3.62(3.80*) 12A 3.615 0.10 3.64* 95.4 2.8 3.39 95.6 4.00 3.39 87.5 3.5 3.50(3.70) 12B 3.627 0.20 3.62* 95.6 2.8 3.38 96.4 4.00 3.37 89.3 3.3 3.50(3.69*) 12C 3.078 15.00  3.61* 95.6 18.4  3.38 96.5 20.30 3.37 87.2 20.33.50 (3.69*) 13 3.660 0.10 94.7 2.6 3.41 93.8 4.00 3.42 86.7 3.6 3.50(3.70*) 4A 3.676 None 3.03 100.4 None 3.03 101.0 0.1 3.07 (3.54*) 4B3.618 0.10 3.02 101.4 None 3.02 101.4 0.1 3.05 (3.56*) 4C 3.632 0.103.01 100.4 None 3.01 102.4 0.1 3.11 (3.57*) 5A 3.746 None 3.04 101.9None 3.04 102.2 0.1 3.06 (3.57*) 5B 3.770 None 3.04 101.7 None 3.02102.3 0.1 3.05 (3.54*) 5C 3.732 None 3.02 102.3 None 3.01 101.6 0.1 3.02(3.54*) *pH of docetaxel diluted solution.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1. A non-aqueous, ethanol-free taxane liquid nanodispersion formulationcomprising: a taxane; an oil; a non-ionic surfactant; a non-aqueoussolvent; and an organic acid component; wherein the organic acidcomponent is soluble in the non-aqueous solvent and the amount by weightof non-ionic surfactant is equal to or greater than the amount by weightof non-aqueous solvent.
 2. The nanodispersion formulation according toclaim 1, wherein the taxane is present in an amount ranging from about0.5 to about 5 wt %.
 3. The nanodispersion formulation according toclaim 1, wherein the taxane is present in about 2 wt %.
 4. Thenanodispersion formulation according to claim 1, wherein the taxane ispaclitaxel.
 5. The nanodispersion formulation according to claim 1,wherein the taxane is docetaxel.
 6. The nanodispersion formulationaccording to claim 3, wherein the taxane is anhydrous docetaxel.
 7. Thenanodispersion formulation according to claim 3, wherein the taxane isdocetaxel trihydrate.
 8. The nanodispersion formulation according toclaim 1, wherein the oil is selected from the group consisting ofsynthetic oils, vegetable oils, tocopherols and combinations thereof. 9.The nanodispersion formulation according to claim 8, wherein the oil isselected from the group consisting of soybean oil, olive oil, sesameoil, corn oil, a medium chain triglyceride, a tocopherol or derivativethereof and combinations thereof.
 10. The nanodispersion formulationaccording to claim 1, wherein the oil is present in an amount rangingfrom about 1 to about 20 wt %.
 11. The nanodispersion formulationaccording to claim 10, wherein the oil is soybean oil.
 12. Thenanodispersion formulation according to claim 11, wherein the soybeanoil is present in an amount ranging from about 1 to about 5 wt %. 13.The nanodispersion formulation according to claim 10, wherein the oil isa medium chain triglyceride.
 14. The nanodispersion formulationaccording to claim 13, wherein the medium chain triglyceride is presentin an amount ranging from about 1 to about 5 wt %.
 15. Thenanodispersion formulation according to claim 1, wherein the non-ionicsurfactant is present in an amount ranging from about 40 to about 75 wt%.
 16. The nanodispersion formulation according to claim 15, wherein thenon-ionic surfactant is present in an amount ranging from about 50 toabout 60 wt %.
 17. The nanodispersion formulation according to claim 1,wherein the non-ionic surfactant is polysorbate
 80. 18. Thenanodispersion formulation according to claim 1, wherein the non-aqueoussolvent is present in an amount ranging from about 20 to about 60 wt %.19. The nanodispersion formulation according to claim 18, wherein thenon-aqueous solvent is present in an amount ranging from about 35 toabout 45 wt %.
 20. The nanodispersion formulation according to claim 1,wherein the non-aqueous solvent is polyethylene glycol.
 21. Thenanodispersion formulation according to claim 20, wherein thepolyethylene glycol has a melting point of less than 0° C.
 22. Thenanodispersion formulation according to claim 1, wherein the organicacid component is present in an amount ranging from 0.3 to 3 wt %. 23.The nanodispersion formulation according to claim 22, wherein theorganic acid component is present in an amount ranging from 0.5 to 1 wt%.
 24. The nanodispersion formulation according to claim 1, wherein theorganic acid component is an organic acid.
 25. The nanodispersionformulation according to claim 24, wherein the organic acid is selectedfrom the group consisting of lactic acid and acetic acid.
 26. Thenanodispersion formulation according to claim 25, wherein the organicacid is lactic acid.
 27. The nanodispersion formulation according toclaim 26, wherein the lactic acid is present in about 0.8 wt %.
 28. Thenanodispersion formulation according to claim 1, wherein the organicacid component is an organic acid buffer.
 29. The nanodispersionformulation according to claim 28, wherein the organic acid buffer islactic acid buffer.
 30. The nanodispersion formulation according toclaim 29, wherein the lactic acid buffer is present in about 1 wt %. 31.The nanodispersion formulation according to claim 1, wherein the amountby weight of oil is equal to or less than about 2.5 times the amount oftaxane.
 32. The nanodispersion formulation according to claim 1, whereinthe ratio by weight of taxane to oil is from about 1:0.5 to about 1:2.5.33. A non-aqueous, ethanol-free docetaxel liquid nanodispersionformulation comprising: docetaxel; soybean oil in an amount ranging fromabout 1 to about 5 wt %; polysorbate 80 in an amount ranging from about50 to about 60 wt %; polyethylene glycol in an amount ranging from about35 to about 45 wt %; and lactic acid or lactic acid buffer in an amountranging from 0.3 to 1 wt %; wherein the amount by weight of non-ionicsurfactant is about equal to or greater than the amount by weight ofnon-aqueous solvent.
 34. A non-aqueous, ethanol-free docetaxel liquidnanodispersion formulation comprising: docetaxel; a medium chaintriglyceride in an amount ranging from about 1 to about 5 wt %;polysorbate 80 in an amount ranging from about 50 to about 60 wt %;polyethylene glycol in an amount ranging from about 35 to about 45 wt %;and lactic acid or lactic acid buffer in an amount ranging from 0.3 to 1wt %; wherein the amount by weight of non-ionic surfactant is aboutequal to or greater than the amount by weight of non-aqueous solvent.35. The nanodispersion formulation according to claim 33, wherein thedocetaxel is anhydrous docetaxel.
 36. The nanodispersion formulationaccording to claim 33, wherein the docetaxel is docetaxel trihydrate.37. The nanodispersion formulation according to claim 33, wherein thedocetaxel is present in an amount ranging from about 0.5 to about 5 wt%.
 38. The nanodispersion formulation according to claim 37, wherein thedocetaxel is present in about 2 wt %.
 39. The nanodispersion formulationaccording to claim 33, wherein the polyethylene glycol has a meltingpoint of less than 0° C.
 40. The nanodispersion formulation according toclaim 33, wherein the ratio by weight of docetaxel to oil is from 1:0.5to 1:2.5.
 41. The nanodispersion formulation according to claim 1,wherein the ethanol-free taxane liquid nanodispersion formulation has apH of less than about 3.5.
 42. The nanodispersion formulation accordingto claim 1, wherein the formulation is stable for more than 6 months at40° C.
 43. The nanodispersion formulation according to claim 1, whereinthe formulation exhibits a taxane recovery rate of greater than 95%after 6 months at 40° C.
 44. The nanodispersion formulation according toclaim 1, wherein the formulation forms particles of less than about 20nm when combined with an aqueous medium.
 45. A method of administeringan ethanol-free taxane liquid nanodispersion formulation to a subject,the method comprising: (a) combining the ethanol-free taxanenanodispersion formulation according to any one of the above claims withan aqueous medium to provide an ethanol-free taxane diluted solution;and (b) administering the ethanol-free taxane diluted solution to thesubject.
 46. A kit comprising: (a) a vial containing the ethanol-freetaxane nanodispersion formulation according to claim 1; and (b)instructions for using the ethanol-free taxane nanodispersionformulation.
 47. The kit according to claim 46, further comprising (c)an aqueous medium.